ClinVar Miner

Submissions for variant NM_022455.4(NSD1):c.6426C>G (p.Tyr2142Ter) (rs1060501493)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000474368 SCV000546552 pathogenic Beckwith-Wiedemann syndrome 2016-12-30 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the penultimate exon of the NSD1 mRNA at codon 2142 (p.Tyr2142*). While this is not anticipated to result in nonsense-mediated decay, it is expected to delete the last 555 amino acids of the NSD1 protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a NSD1-related disease. This variant would result in the deletion of the last 555 amino acids of the NSD1 protein, including the entire PHD6 (C5HCH) domain that has been shown to be required for the interaction with Nizp1. Furthermore, many deleterious missense variants located in this domain have been reported in individuals affected with Sotos syndrome (PMID: 15942875, 21972110, 12464997). In addition, truncating variants downstream of this variant (such as p.Arg2187*, and c.7514delA) have been determined to be pathogenic (PMID: 16247291, 15742365). This suggests that deletion of this region of the NSD1 protein causes disease. For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197907 SCV001368690 pathogenic Obesity; High palate; Tall stature; Overgrowth; Hypermetropia; Pes planus; Abnormality of the ribs; Downslanted palpebral fissures; Macrocephalus; Soft, doughy skin; Intellectual disability; Advanced ossification of carpal bones; Increased body weight 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. This variant was detected in heterozygous state.

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